5'-Adenosine Monophosphate Shows Neuroprotective Potential, Paving New Avenues for Hypoxic‑Injury Drugs

A basic study published in Shock reveals that the natural metabolite 5'-adenosine monophosphate (AMP) induces a hypometabolic state by suppressing mitochondrial metabolism and cutting oxygen consumption, offering a novel intervention strategy for organ injuries caused by ischemia and hypoxia. Ischemia‑reperfusion injury triggered by cardiac arrest or severe trauma frequently leads to irreversible brain damage. Clinical therapeutic hypothermia works slowly, limiting its use in critical‑care scenarios.

Animal experiments demonstrate that intraperitoneal AMP injection rapidly lowers mice’s body temperature, heart rate and respiratory rate, triggering a torpor‑like hypometabolic state. All physiological indicators recover spontaneously without long‑term neurological damage. In vitro neuronal tests show AMP raises intracellular AMP concentrations, activates the AMPK pathway and inhibits mTORC1, down‑regulating mitochondrial calcium signals to directly reduce neuronal mitochondrial respiration. This protective effect is independent of adenosine‑dependent signaling.

In hypoxic models, AMP pre‑treatment nearly doubles mice’s survival time under low‑oxygen conditions. It disrupts the ATP‑driven P2‑receptor autocrine signaling loop and breaks the positive feedback sustaining high mitochondrial metabolism, thereby lowering cellular oxygen consumption. As an endogenous metabolite, AMP has lower toxicity compared with drug candidates such as hydrogen sulfide.

Industry analysts note AMP holds promise for emergency protection in trauma, stroke and cardiac arrest to buy time for organ reperfusion. Nevertheless, efficacy validation in large animals is required before further translational research.

FOR DETAIL: https://doi.org/10.1097/SHK.0000000000001440

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